Our leadership team of veteran investigators propose 3 projects to address the currently most preventable sources of postinjury mortality: trauma induced coagulopathy (TIC) and morbidity: delayed lung dysfunction in survivors. We are encouraged to be part of the culture that helped dwindle the incidence of Multiple Organ Failure, MOF, in a decade. An experienced Administration Core will execute this program as before. By combining salient discoveries in each previous project, breakthroughs in point of care research, enabled by SIMP Core and guided by clinical data in the HS Core, we identify the most important questions and testable hypotheses. Projects 1, 2 and 3 anchor themselves on coagulative functionality, proteomics and metabolomics on matched patient samples and then continue to derive experimental approaches Project 1 The leadership team consisting of Drs. Moore, Silliman, Sauaia and Banerjee examine fibrinolytic phenotypes that contribute to acute mortality. They hypothesize that hemorrhagic shock predisposes to hyperfibrinolysis, but tissue injury causes fibrinolysis shut-down, due to regulation of plasminogen/plasmin. The hypotheses are tested in animal models of shock and with high content data on patients. Project 2 The leadership team consisting of Drs. Silliman, Banerjee, Hansen, Moore, Sauaia and Dziecatowskowa designed these aims to investigate novel regulators of plasmin found in post traumatic plasma. They focus on proteins containing (kringles, calponin or fibronectin) domains that become abundant after blood storage, or in conditions of hemorrhagic shock versus tissue injury, and appear to be novel regulators of human plasmin. Project 3 The leadership team consisting of Drs. D'Alessandro, Peltz, Banerjee, Silliman, Moore, and Sauaia designed these aims to specifically understand anionic contributors to plasma acidity (Aim1). They hypothesize that trauma and hemorrhagic shock instigate different metabolic changes resulting in systemic pathology, which can be identified by metabolomics analysis. They assess the role of elevated succinate and glutamine metabolism (Aim2) and potential microbially generated metabolites, for Next-Gen resuscitation therapy. These aims will lead to pragmatically attenuating acute mortality and survivor morbidity within the next decade, are supported by an active HS core that verifies scientific mechanisms and a SIMP Core and Administration Core that ensure capability.